Host adaptive immunity deficiency in severe pandemic influenza

被引：131

作者：

Bermejo-Martin, Jesus F. ^{[1
,2
]}

Martin-Loeches, Ignacio ^{[3
]}

Rello, Jordi ^{[4
]}

Anton, Andres ^{[5
]}

Almansa, Raquel ^{[1
,2
]}

Xu, Luoling ^{[6
]}

Lopez-Campos, Guillermo ^{[7
]}

Pumarola, Tomas ^{[5
]}

Ran, Longsi ^{[6
]}

Ramirez, Paula ^{[8
]}

Banner, David ^{[6
]}

Ng, Derek Cheuk ^{[6
]}

Socias, Lorenzo ^{[9
]}

Loza, Ana ^{[10
]}

Andaluz, David ^{[11
]}

Maravi, Enrique ^{[12
]}

Gomez-Sanchez, Maria J. ^{[12
]}

Gordon, Monica ^{[8
]}

Gallegos, Maria C. ^{[13
]}

Fernandez, Victoria ^{[13
]}

Aldunate, Sara ^{[12
]}

Leon, Cristobal ^{[10
]}

Merino, Pedro ^{[14
,15
]}

Blanco, Jesus ^{[14
,15
]}

Martin-Sanchez, Fernando ^{[7
]}

Rico, Lucia ^{[1
,2
]}

Varillas, David ^{[1
,2
]}

Iglesias, Veronica ^{[1
,2
]}

Angeles Marcos, Maria ^{[5
]}

Gandia, Francisco ^{[11
]}

Bobillo, Felipe ^{[11
]}

Nogueira, Begona ^{[2
]}

Rojo, Silvia ^{[2
]}

Resino, Salvador ^{[16
]}

Castro, Carmen ^{[17
]}

Ortiz de Lejarazu, Raul ^{[1
,2
]}

Kelvin, David ^{[6
,18
,19
]}

机构：

[1] Hosp Clin Univ IECSCYL, Infect & Immun Unit, Valladolid 47005, Spain

[2] Hosp Clin Univ SACYL, Microbiol & Immunol Serv, Valladolid 47005, Spain

[3] Joan XXIII Univ Hosp SEMICYUC, Crit Care Dept, Tarragona 43007, Spain

[4] CIBERES SEMICYUC, Crit Care Dept, Area Gen Hosp Vall Hebron, Inst Recerca,Vall Hebron UAB, Barcelona 08035, Spain

[5] Univ Barcelona, Microbiol Serv, Hosp Clin, IDIBAPS, E-08036 Barcelona, Spain

[6] Univ Hlth Network, Toronto, ON M5G 1L7, Canada

[7] Inst Salud Carlos III, Med Bioinformat Dept, Madrid, Spain

[8] Hosp Univ La Fe SEMICYUC, Crit Care Dept, Valencia 46009, Spain

[9] Hosp Son Llatzer SEMICYUC, Crit Care Dept, Palma de Mallorca 07198, Spain

[10] Hosp N Sra Valme SEMICYUC, Crit Care Dept, Seville 41014, Spain

[11] Hosp Clin Univ SACYL SEMICYUC, Crit Care Dept, Valladolid 47005, Spain

[12] Hosp Virgen Camino SEMICYUC, Crit Care Dept, Pamplona 31008, Spain

[13] Hosp Son Llatzer, Microbiol Serv, Palma de Mallorca 07198, Spain

[14] Hosp Univ Rio Hortega SACYL SEMICYUC, Crit Care Dept, Valladolid 47012, Spain

[15] Inst Salud Carlos III, CIBER Enfermedades Resp, Valladolid 47012, Spain

[16] Inst Salud Carlos III, Lab Mol Epidemiol Infect Dis, Natl Ctr Microbiol, Madrid, Spain

[17] Hosp N Sra Valme, Microbiol Serv, Seville 41014, Spain

[18] Shantou Univ, Int Inst Infect & Immun, Shantou 515031, Guangdong, Peoples R China

[19] Univ Sassari, I-07100 Sassari, SS, Italy

来源：

CRITICAL CARE | 2010年 / 14卷 / 05期

关键词：

CD8(+) T-CELLS; A H1N1 VIRUS; INNATE; RESPONSES; INDUCTION; INFECTION; PHASE;

D O I：

10.1186/cc9259

中图分类号：

R4 [临床医学];

学科分类号：

1002 ; 100602 ;

摘要：

Introduction: Pandemic A/H1N1/2009 influenza causes severe lower respiratory complications in rare cases. The association between host immune responses and clinical outcome in severe cases is unknown. Methods: We utilized gene expression, cytokine profiles and generation of antibody responses following hospitalization in 19 critically ill patients with primary pandemic A/H1N1/2009 influenza pneumonia for identifying host immune responses associated with clinical outcome. Ingenuity pathway analysis 8.5 (IPA) (Ingenuity Systems, Redwood City, CA) was used to select, annotate and visualize genes by function and pathway (gene ontology). IPA analysis identified those canonical pathways differentially expressed (P < 0.05) between comparison groups. Hierarchical clustering of those genes differentially expressed between groups by IPA analysis was performed using BRB-Array Tools v.3.8.1. Results: The majority of patients were characterized by the presence of comorbidities and the absence of immunosuppressive conditions. pH1N1 specific antibody production was observed around day 9 from disease onset and defined an early period of innate immune response and a late period of adaptive immune response to the virus. The most severe patients (n = 12) showed persistence of viral secretion. Seven of the most severe patients died. During the late phase, the most severe patient group had impaired expression of a number of genes participating in adaptive immune responses when compared to less severe patients. These genes were involved in antigen presentation, B-cell development, T-helper cell differentiation, CD28, granzyme B signaling, apoptosis and protein ubiquitination. Patients with the poorest outcomes were characterized by proinflammatory hypercytokinemia, along with elevated levels of immunosuppressory cytokines (interleukin (IL)-10 and IL-1ra) in serum. Conclusions: Our findings suggest an impaired development of adaptive immunity in the most severe cases of pandemic influenza, leading to an unremitting cycle of viral replication and innate cytokine-chemokine release. Interruption of this deleterious cycle may improve disease outcome.

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